A brief introduction to population genetics

1. Hasan Alhaddad, Ph.D.
Guest lecturer: Molecular Genetics (342)
In Faculty of Allied Health Sciences (LT2-123)
April 1st 2015 (12:30 - 2:30)
A Brief Introduction to Population
Genetics

2. AIMS
• Review Mendelian genetics and its relation to
population genetics.
• Review evolution and its relation to population
genetics.
• Introduce the field of population genetics and
its significance.
• Introduce the most basic model in population
genetics (HW equation).
• Run some beanbag experiments.

3. Who am I?
• My name is Hasan Alhaddad.
• Ph.D. in Genetics from UC Davis.
• I studied insects and cats and I do population
and evolutionary genetics for fun.
• I love science and I like to share this love with
everybody especially you.

4. Who am I?
• Check my website for more information or if you
need to contact me.
hagenetics.org

5. Population genetics
Population
Genetics
Evolutionary biologyMolecular Biology
Mendelianism
DNA
RNA
protein
Darwinism
dominant
recessive
co-dominant
mutation
mutation
species
neo-darwinism
genetic drift
mutation rate
substitution
deletion
natural selection
speciation
fitness
reproduction
survival
insertion transversion
transition
allele frequency
selection
gene
allele
Mendeldiscrete
continuous
locus
loci
chromosome
different by state
identical by state
variation
polymorphism
homozygous
heterozygous
segregation
monomorphic
morphology
haploid
diploid
biallelic
multi-allelic
Darwin
immigration
migration
isolation
population
phlyogenetics
phylogeny
taxonomy
genotype
phenotype
A
T C
G
U
replication
transcription
translation
population structure
genotype frequency
N
2N
pangenesis
hybridization
blending inheritance
visual traits
biochemical traits
Mendel’s first law
Mendel’s second law
Fst
Fis
Inbreeding
inbreeding depression
mRNA
tRNA
rRNA
gene expression
splicing
P
F1
F2 filial generation
parental generation
adaptation
polyploidy
recombination rate
Fisher
Wright
sympatric speciation
allopatric speciation
genome
chromatin
histone
H3
H4
H2A
H2B
LD
Ne
generation
p
q
2pq
variance
continous
epigenetics
motif
cis
trans
promoter
exon
intron
transcriptome
proteome
double helix
bp
Kb
Mb
Gb
nucleotide
amino acid
alpha helix
Beta sheet

6. Population genetics is the field that results
from combining Genetics and Evolution
We need to review both genetics and
evolution to properly cover concepts
pertain to population genetics

7. Traditions of Genetics
Natural selection of
small changes
Darwin Mendel
Transmission of large
differences
Evolution and
Population Genetics
Analytical Genetics

8. Traditions
of
Genetics
Pearson
Darwin Mendel
Biometricians Mendelists
Yule Punnett Bateson
Hardy Weinberg
“one cannot help feeling that the
speculations would have had more
value had he kept his emotions under
better control; the style and method of
the religious revivalist are ill-suited to
scientific controversy” (Edwards, 2008)
Yule to Bateson (1902)

9. Mendel and the general theory of
inheritance and basic laws

10. The chief motives to
understand heredity and
the bases of it were:
1. Speciation
2. Hybridization
3. Similarities between
parents and offsprings
Scientific motives

11. What were the theories of inheritance at
the time?

12. Theories of inheritance
Before Mendel the only proposed theory of
inheritance was “blending inheritance”

13. Theories of inheritance
How traits are passed on?
Two hypotheses

14. Theories of inheritance
What happens to characters when they are
blended every generation?

15. Theories of inheritance
Darwin’s hypothesis of Pangenesis
“Gemmules” travel from every part
of the body to the reproductive
system to pass the traits to future
generation.
Hypothesis NOT supported by
scientific evidence.
O'Connor, C. & Miko, I. (2008) Developing the chromosome theory. Nature Education 1(1):44

16. Mendel and his peas
Gregor Mendel (Johann) studied heredity by the
systematic breeding experiments of garden pea
(Pisum sativum)

17. Why Pea plants?
Clear and distinct visual Traits/characters
Mendel’s Peas

18. What kind of traits/characters are these?
Why should we care?

19. Traits and characters
Traits can be continuous or discontinuous
(also called discrete)

20. Traits

21. OK!?
What is the connection to Darwin and
Mendel?

22. Mendel’s characters vs. Darwin’s
Mendel focused on variation of large effect while
Darwin observed small variations that affect fitness

23. Lost?
Do not worry
We will get to Darwin in a bit

24. Mendel’s discrete characters
Mendel chose seven discrete characters that
can be easily be visualized and identified.
Miko, I. (2008) Gregor Mendel and the principles of inheritance. Nature Education 1(1):134

25. Mendel’s pure single trait lines
1) Establish pure lines of each character
Which characters?

26. What are pure lines?
Homozygous?
Identical by state?

27. 2) Cross breed the pure lines.
3) Resulting plants are hybrids.
4) Inspect the phenotypes of the first generation.
How do we inspect the phenotype?
Why?
First generation

28. Observations and findings:
• All resulting plants exhibits the phenotype of
one of the parents.
• One of the parental phenotypes disappears in
the first hybrid generation.
First generation

29. 5) Self cross the F1 individuals.
6) Inspect the phenotypes of the resulting F2
generation.
Second generation

30. How did Mendel inspect the phenotypes of the F2
generation?
Second generation

31. Mendel’s monohybrid results

32. Observations and findings:
• The selfing of the first generation results in the
reappearance of one of the parents’
characteristics.
• A factor/particle is within the plant that results
in the appearance of the plant.
• Both male and female contribute equally to the
phenotype.
• The absence or appearance of a specific
character depends on the combination of
factors.
Mendel’s Monohybrid Experiment

33. Observations and findings:
• The “factor” that
appeared in all
individuals of the first
generation is the
“dominant” factor.
• The “factor” that
disappeared in the first
generation is the
“recessive” factor.
Factor’s type

34. • The P generation is a pure bred contains each with two
factors of the same type (homozygous).
• The F1 generation is a hybrid and as a result contains
two different “factors” one from each of the parents
(heterozygous).
Genotype

35. • “Factors” within a plant
separate during the
formation of gametes.
• “Factors” unite during
fertilization randomly.
• The phenotype of resulting
union is determined by the
combination of factors.
Segregation of factors
(alleles)
Mendel’s 1st law

36. • Yellow : Green
3:1
• Round : Wrinkled
3:1
What is the ratio of
each phenotype
independently?
Mendel’s 2nd law
• Each factor segregate independently.
Independent Assortment

37. • What is “dominant” and “recessive” a description of?
• What is a phenotype?
• What is a genotype?
• What is a homozygous?
• Identical by state?
• What is a heterozygous?
• Different by state?
• Did Mendel observe or infer genotype?
• Did Mendel observe or infer phenotype?
Review

38. Genes and Genotype

39. What is an allele?
Alleles are Mendel’s factors that he could not
see but infer by crosses
Do not get it?
They are the (A) and (a) that are being passed
into gametes and unite to give the genotype of
an individual.

40. What is an allele?

41. Alleles on chromosomes?
Where?
Same location?
Same chromosome?

42. Locus
• A specific location in the genome is called
locus (plural loci).
• Alleles at the same locus are inherited each
from one parent.

43. Alleles at a locus
• DNA at a specific locus
may differ in one
individual.
• How?
• What are the alleles in
the figure?

44. Mendel’s work
Important contributions
by Mendel to biology:
1.Genotypic notation.
2.Quantitative framework.

45. Now we need to review some evolution
What is evolution?
What is to evolve?

46. Evolution in general
Change through time
Non-biological Biological
Is evolution a fact or a theory?
Evolution (biological and non-biological) is a
fact that is explained by theories
Not buying it?

47. Evolution in general
Can you think of a theory that
explains the evolution of:
1) Food and cuisine (ex.
Machboos)
2) Cars (ex. Ferrari)
3) Houses and cities (ex.
skyscrapers)
4) Clothes and fashion (ex.
Deshdasha)

48. So what about biological evolution?
Let’s start with the theory before Darwin

49. Lamarckian inheritance and evolution
Jean Baptiste Lamarck
Lamarck proposed the
inheritance of acquired
characteristics

50. Testing Lamarck’s idea
August F. Weismann
• Weismann tested Lamarck’s
idea using mice.
• Cutting mice tails and
breeding them.
• 5 generations!
What happened?

51. Natural selection
Darwin and Wallace, independently, proposed a
theory of biological evolution and called it
“Natural selection”
Charles Darwin Alfred Russel Wallace

52. Variation!

53. 1) Individuals within a
population are variable.
2) Variation is heritable
(passed to offsprings).
3) Differential survival and
reproduction.
4) Survival and reproduction
is not random (individuals
with best variation produce
more offsprings).
Natural selection

54. It is all about variation!

55. Did Darwin answer where variation come from?
Did he know about heredity?
Did he know about genes/factors?
Did evolutionary biology stop and end with Darwin’s
theory?
Is natural selection the only force of evolution?
The field of evolutionary biology has itself evolved
and evolutionary studies have gone way beyond
Darwin

56. Population genetics is the answer

57. Some significance
“Nothing in biology
makes sense except in
the light of evolution”
Theodosius Dobzhansky, 1973

58. Some significance
“Nothing in evolution
makes sense except in
the light of population
genetics”
Jeffrey Ross-Ibarra
(2010 citing his mentor)

59. It is the study of the evolutionary historical
record of a group of individuals documented
in the DNA of their descendants
What is population genetics?

60. Why population genetics?
1) Understand and refine theory

61. Why population genetics?
2) Understand the history of genes
Opazo, J. C., Hofmann, F. G. & Storz, J. F. (2008) Genomic evidence for independent origins of β-like
globin genes in monotremes and therian mammals. Proceedings of the National Academy of Sciences
(105): 1590–1595

62. Why population genetics?
3) Understand the history of populations/
organisms
21. J. Parsonnet, in Microbes and Malignancy, J. Parsonnet,
Ed. (Oxford Univ. Press, New York, 1999), pp. 3–18.
22. Y. Xu et al., Genomics 81, 329 (2003).
23. We thank the National Cancer Institute–supported
Cooperative Human Tissue Network for tissues used
in this study, M. Aquafondata for tissue staining,
P. S. Schnable for sharing cDNA data sets used in DTS
pilot testing, O. Gjoerup and R. D. Wood for helpful
comments, and J. Zawinul for help with the manuscript.
Supported in part by funds from NIH R33CA120726
and the Pennsylvania Department of Health. The
Pennsylvania Department of Health specifically
disclaims responsibility for any analyses, interpretations,
or conclusions.
Supporting Online Material
www.sciencemag.org/cgi/content/full/1152586/DC1
Materials and Methods
Figs. S1 to S3
Tables S1 to S5
References
5 November 2007; accepted 8 January 2008
Published online 17 January 2008;
10.1126/science.1152586
Include this information when citing this paper.
Worldwide Human Relationships
Inferred from Genome-Wide
Patterns of Variation
Jun Z. Li,1,2
*† Devin M. Absher,1,2
* Hua Tang,1
Audrey M. Southwick,1,2
Amanda M. Casto,1
Sohini Ramachandran,4
Howard M. Cann,5
Gregory S. Barsh,1,3
Marcus Feldman,4
‡
Luigi L. Cavalli-Sforza,1
‡ Richard M. Myers1,2
‡
Human genetic diversity is shaped by both demographic and biological factors and has fundamental
implications for understanding the genetic basis of diseases. We studied 938 unrelated individuals
from 51 populations of the Human Genome Diversity Panel at 650,000 common single-nucleotide
polymorphism loci. Individual ancestry and population substructure were detectable with very high
resolution. The relationship between haplotype heterozygosity and geography was consistent with
the hypothesis of a serial founder effect with a single origin in sub-Saharan Africa. In addition, we
observed a pattern of ancestral allele frequency distributions that reflects variation in population
dynamics among geographic regions. This data set allows the most comprehensive characterization
to date of human genetic variation.
I
n the past 30 years, the ability to study DNA
sequence variation has dramatically increased
our knowledge of the relationships among
and history of human populations. Analyses of
limited populations, or both, and yield an in-
complete picture of the relative importance of
mutation, recombination, migration, demogra-
phy, selection, and random drift (7–10). To
Europe, the Middle East, South/Central Asia,
East Asia, Oceania, and the Americas (11). This
data set is freely available (12) and allows a
detailed characterization of worldwide genetic
variation.
We first studied genetic ancestry of each
individual without using his/her population
identity. This analysis considers each person’s
genome as having originated from K ancestral
but unobserved populations whose contributions
are described by K coefficients that sum to 1 for
each individual. To increase computational effi-
ciency, we developed new software, frappe, that
implements a maximum likelihood method (13)
to analyze all 642,690 autosomal SNPs in 938
unrelated and successfully genotyped HGDP-
CEPH individuals (14). Figure 1A shows the
results for K = 7; those for K = 2 through 6 are in
fig. S1. At K = 5, the 938 individuals segregate
into five continental groups, similar to those re-
1
Department of Genetics, Stanford University School of
Medicine, Stanford, CA 94305–5120, USA. 2
Stanford
Human Genome Center, Stanford University School of
Medicine, Stanford, CA 94305–5120, USA. 3
Department of
Pediatrics, Stanford University School of Medicine, Stanford,
4
Various body site tissues
Total MCV negative (%) 54/59 (92)
Total MCV positive (%) 5/59 (8)
Appendix control 1 –/+
Appendix control 2 –/+
Gall bladder –/+
Bowel –/+
Hemorrhoid –/+
Skin and skin tumor tissues
Total MCV negative (%) 21/25 (84)
Total MCV positive (%) 4/25 (16)
Skin –/+
KS skin tumor 1 –/+
KS skin tumor 2 –/+
KS skin tumor 3 –/+

63. Why population genetics?
4) Understand the relationship between organisms

64. Why population genetics?
5) Classify groups of living
organisms

65. Why population genetics?
6) Understand the evolutionary forces that
shape life forms

66. Why population genetics?
7) Reconstruct the history and the timing of
evolutionary events

67. Why population genetics?
8) Find cool stuff!
Genome-wide
Association studies
(GWAS)

68. Redefining evolution
Evolution is the change in allele frequency at a
locus in a population over time
Change in frequency Time
Allele frequencies?
populations?
Evolutionary forces act on an individuals,
correct?
Why populations?

69. Redefining evolution
Evolutionary forces act on the individuals but
the affects are seen in populations in the form
of changes in allele frequency
So what exactly do we do?
We study the effects of evolutionary forces on
the frequency of a mutant allele
Ya Rabbi
What are all these terms?
I am lost

70. Redefining evolution
One more thing about the changes
Molecular changes vs. Morphological changes
Small effects on fitness large effects on fitness
If they have small effects, then we will
have to deal with chance
We need models to understand
stochastic/random forces
vs.

71. (1)
Edwards,
2008
Hardy-Weinberg Principle
“ The answer was in Mendel’s paper all the time”1
The first and most basic model in population genetics

72. Hardy-Weinberg Law
Weinberg Hardy
• Wilhelm Weinberg
• (1862-1937)
• German Physician
• Godfrey H. Hardy
• (1877-1947 )
• English mathematician

73. (1) Edwards, 2008 (2) Jewett,1914
How did a mathematician, Hardy, get involved?
• February 28th 1908, Punnett gave a
lecture on “Mendelism in relation to
disease” 1.
•The lecture discusses brachydactylism.
• Brachydactylism means short-
fingeredness 2.
• Shortness in fingers and toes relative to
other body parts.
• The genetics disease is a dominant trait.

74. (1) Edwards, 2008
• Yule: if brachydactyl is a dominant trait
(assuming random mating) ➔ 3:1
brachydactyl : normal. 1
• Yule misinterpreted Mendel’s theory. In
order to get the 3:1 ratio, the gene
frequency must be ½.
• Punnett: interpreted Yules remarks as
“why the nation was not becoming …..
Brachydactylous”. 1
• Punnett was puzzled “why the dominant
did not continually increase in frequency?”
1
• Hardy ….. Help!
How did a mathematician, Hardy, get involved?

75. (1) Hardy, 1908
Mendelian Proportions in a Mixed Population 1
• Assumptions: Aa is a Mendelian characters. The
numbers of genotypes pure dominant (AA), heterozygotes
(Aa), and pure recessives (aa) are 1:2:1 respectively.
• Conditions: “ … suppose that the numbers are fairly
large, so that mating may be regarded as random, that the
sexes are evenly distributed among the three varieties, and
that all are equally fertile.”1
• Using “a little mathematics …” the allele frequencies in the
next generation will be “ .. unchanged after the second
generation.”
• “ I have … considered only the very simplest hypotheses
possible.” 1

76. Assumptions
• Single locus / Biallelic locus
• Diploid organism / Equal sexes.
• No natural selection: equal survival rates and
reproductive success
• No mutation: no alleles created or converted
• No migration/gene flow: individuals do not
move into or out of the population

77. Assumptions
• No genetic drift.
• Population is infinitely large: sampling errors
and random effects insignificant.
• No population subdivision.
• Random mating (no inbreeding).
• Non overlapping generations.

78. The idea
Allele 2
(a)
Allele 1
(A)
Single locus and two alleles
q = frequency of Allele 2
q =
p = frequency of Allele 1
p =
What is the frequency of all alleles in a population?
p + q =
# of allele 1
# allele 1+allele 2
# of allele 2
# allele 1+allele 2
# of allele 1
# allele 1+allele 2
# of allele 2
# allele 1+allele 2
+ =
# allele 1+allele 2
# allele 1+allele 2

79. Hardy-Weinberg Principle
(1) p + q = 1
A
(p)
a (q)
a
(q)
AA (p2) Aa (pq)
Aa (pq) aa (q2)
(2) p2+2pq+q2=1
Predictions
(1) Allele frequency do not change over time
(2) Genotype frequencies can be calculated
A (p)

80. (1) Klug et al., Concepts of Genetics
Relationship between genotype and allele frequency 1
p2+ 2pq + q2 =1
p2 = (0.8)2 = 0.64
2pq = 2*(0.8)*(0.2) =
0.32
q2 = (0.2)2 = 0.04
Population is at HW equilibrium at this locus

81. What happens in frequencies ARE NOT
in HW equilibrium?
We test which assumption of HW was
violated and may, as a result, explain the
evolution of the population at this
particular locus

82. Not so brief introduction after all
Sorry :-)

83. REPRINTS AND REFLECTIONS
A Defense of Beanbag Genetics*
JBS Haldane
My friend Professor Ernst Mayr, of Harvard
University, in his recent book Animal Species and
Evolution1
, which I find admirable, though I disagree
with quite a lot of it, has the following sentences on
page 263.
The Mendelian was apt to compare the genetic
contents of a population to a bag full of colored
beans. Mutation was the exchange of one kind
of bean for another. This conceptualization has
been referred to as ‘‘beanbag genetics’’. Work in
population and developmental genetics has shown,
however, that the thinking of beanbag genetics
is in many ways quite misleading. To consider
genes as independent units is meaningless from
the physiological as well as the evolutionary
viewpoint.
Any kind of thinking whatever is misleading out
of its context. Thus ethical thinking involves the
concept of duty, or some equivalent, such as right-
eousness or dharma. Without such a concept one is
lost in the present world, and, according to the
religions, in the next also. Joule, in his classical
papers on the mechanical equivalent of heat, wrote
of the duty of a steam engine. We now write of
its horsepower. It is of course possible that
as I have been officially informed that I
for a visa for entering the United State
dead, but when alive preferred attack
Wright is one of the gentlest men I ha
and if he defends himself, will not counte
leaves me to hold the fort, and that by w
than speech.
Now, in the first place I deny that the m
theory of population genetics is at all im
least to a mathematician. On the contr
Fisher, and I all made simplifying assum
allowed us to pose problems soluble by
tary mathematics at our disposal, and e
not always fully solve the simple prob
ourselves. Our mathematics may impre
but do not greatly impress mathematic
give a simple example. We want to kn
frequency of a gene in a population ch
natural selection. I made the following
assumptions3
:
1. The population is infinite, so the
each generation is exactly that calcula
somewhere near it.
2. Generations are separate. This is
minority only of animal and plant s
even in so-called annual plants a fe
Published by Oxford University Press on behalf of the International Epidemiological Association
ß The Author 2008; all rights reserved.
International Journal of Epidemiolog
doi:
REPRINTS AND REFLECTIONS
A Defense of Beanbag Genetics*
JBS Haldane
My friend Professor Ernst Mayr, of Harvard
University, in his recent book Animal Species and
Evolution1
, which I find admirable, though I disagree
with quite a lot of it, has the following sentences on
page 263.
The Mendelian was apt to compare the genetic
contents of a population to a bag full of colored
beans. Mutation was the exchange of one kind
of bean for another. This conceptualization has
been referred to as ‘‘beanbag genetics’’. Work in
population and developmental genetics has shown,
however, that the thinking of beanbag genetics
is in many ways quite misleading. To consider
genes as independent units is meaningless from
the physiological as well as the evolutionary
viewpoint.
Any kind of thinking whatever is misleading out
of its context. Thus ethical thinking involves the
concept of duty, or some equivalent, such as right-
eousness or dharma. Without such a concept one is
lost in the present world, and, according to the
religions, in the next also. Joule, in his classical
papers on the mechanical equivalent of heat, wrote
of the duty of a steam engine. We now write of
its horsepower. It is of course possible that
ethical conceptions will in future be applied to
electronic calculators, which may be given built-in
consciences!
as I have been officially informed that I am ineligible
for a visa for entering the United Statesy
. Fisher is
dead, but when alive preferred attack to defense.
Wright is one of the gentlest men I have ever met,
and if he defends himself, will not counterattack. This
leaves me to hold the fort, and that by writing rather
than speech.
Now, in the first place I deny that the mathematical
theory of population genetics is at all impressive, at
least to a mathematician. On the contrary, Wright,
Fisher, and I all made simplifying assumptions which
allowed us to pose problems soluble by the elemen-
tary mathematics at our disposal, and even then did
not always fully solve the simple problems we set
ourselves. Our mathematics may impress zoologists
but do not greatly impress mathematicians. Let me
give a simple example. We want to know how the
frequency of a gene in a population changes under
natural selection. I made the following simplifying
assumptions3
:
1. The population is infinite, so the frequency in
each generation is exactly that calculated, not just
somewhere near it.
2. Generations are separate. This is true for a
minority only of animal and plant species. Thus
even in so-called annual plants a few seeds can
survive for several years.
3. Mating is at random. In fact, it was not hard to
allow for inbreeding once Wright had given a
Published by Oxford University Press on behalf of the International Epidemiological Association
ß The Author 2008; all rights reserved.
International Journal of Epidemiology 2008;37:435–442
doi:10.1093/ije/dyn056
Let’s do beanbag genetics

84. Let’s do beanbag genetics